Antifungal Prophylaxis and Risk for Invasive Mold Infections in Children with Hematologic Malignancies

Introduction: Invasive mold infections (IMI) are a leading cause of mortality in immunocompromised hosts. Children diagnosed with hematologic malignancies experience profound, prolonged neutropenia following intensive chemotherapy, and are at increased risk for infection-related outcomes. Depending on the anticipated therapeutic intensity, antimicrobial prophylaxis may be employed to mitigate risk for infection. We conducted a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), or lymphoma between 2006-2015 and determined the incidence of IMI to be 4.8% (47/976), with an exceptionally high incidence observed in patients with AML (8.1%). This observation prompted a change in clinical practice that broadened prophylaxis for high risk patients to include coverage of molds, and resulted in development of a risk-stratified algorithm for antifungal prophylaxis in children with hematologic malignancies. The objective of this study was to evaluate the change in IMI incidence post-implementation of this algorithm, and to identify host factors contributing to risk for IMI in children with hematologic malignancies. Objective: The objective was to compare the incidence of IMI pre/post implementation of antifungal prophylaxis decision tree. Also, it was planned to evaluate the impact of race/ethnicity on the development of IMI in children with hematologic malignancies. Methods: We conducted a retrospective review of children ≤ 21 years old and diagnosed with ALL, AML, or lymphoma between 2016-2019, and were treated for IMI between 2016 and June 2020. To identify potential cases, we employed a strategy identical to the one used in the 2006-2015 review, specifically, a search of the electronic medical record utilizing ICD9 codes broadly inclusive of relevant cancer and fungal diagnoses. Each potentially eligible case was then reviewed for the following inclusion/exclusion criteria (also identical to the prior review): diagnosis and treatment of ALL, AML, or lymphoma at Texas Children’s Hospital, diagnosis of IMI that met criteria for ‘proven’ or ‘probable’ per the European Organization for Research and Treatment of Cancer/Mycoses Study Group and occurring prior to stem cell transplant, and no underlying immunodeficiency or history of solid organ transplant. Host and disease-related factors, as well as IMI incidence, were compared for 2006-2015 vs. 2016-2020 using a Chi-square, Fisher, or Student t-test as appropriate, and host factors predictive of IMI were assessed by multivariable linear regression. Results: The overall incidence of proven/probable IMI in children diagnosed with hematological malignancies between 2006-2019 was 4.2% (61/1456). The incidence of IMI decreased from 4.8% to 2.9% between 2006-2015 and 2016-2020. For specific diagnoses, the rate of IMI decreased from 5.0% to 3.6% (ALL, 35/705 vs. 10/276), from 1.9% to 1.4% (lymphoma, 47/976 vs. 14/480), and from 8.1% to 3.2% (AML, 9/111 vs. 2/62). No significant differences in host factor or disease-related characteristics were noted when comparing IMI cases in 2006-2015 vs. 2016-2020, nor were there differences in the proportion of patients in relapse at the time of IMI or taking antifungal prophylaxis. Substantial differences in representative mold species were noted between the two-time periods, e.g. Aspergillus spp. accounted for 19/47 IMI from 2006-2015, but accounted for none of the IMIs diagnosed 2016-2020. In 2016-2020, 5/14 IMI were due to Trichosporon spp., with 4/14 Rhizopus spp., 2/14 Fusarium spp., 1/14 Curvularia spp., 1/14 Histoplasma spp., and 1 that met criteria for probable IMI. In multivariable analyses (Table 1), Hispanics were more likely to develop an IMI than non-Hispanics (p=0.04, OR 1.94, CI 1.03-3.66), and those with lymphoma were less likely to develop an IMI than those with ALL (p=0.03, OR 0.33, CI 0.12-0.87). Patients diagnosed between 2016- 2019 were substantially less likely to develop IMI than those diagnosed 2006-2015 (p=0.003, OR 0.33, CI 0.16-0.69). Discussion and Conclusion: In this single institution study, risk for IMI in children with hematologic malignancies declined significantly after implementation of an antifungal prophylaxis algorithm that broadened coverage for high risk populations. Hispanics were at higher risk for IMI than non-Hispanics, suggesting a need to investigate relevant factors contributing to this disparity. This project can be used to further investigate the factors that contributed to invasive mold infections using a larger study populations. We can then continue to explore the potential contributing factors to the racial and ethnic disparities by including potential contributing factors such as socioeconomic factors and genetic risk

Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents

ABSTRACT We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

A gravitational-wave standard siren measurement of the Hubble constant

The detection of GW170817 (ref. 1) heralds the age of gravitational-wave multi-messenger astronomy, with the observations of gravitational-wave and electromagnetic emission from the same transient source. On 17 August 2017 the network of Advanced Laser Interferometer Gravitational-wave Observatory (LIGO)2 and Virgo3 detectors observed GW170817, a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst event, GRB 170817A, was detected consistent with the LIGO–Virgo sky localization region4–6). The sky region was subsequently observed by optical astronomy facilities7, resulting in the identification of an optical transient signal within about 10 arcseconds of the galaxy NGC 4993 (refs 8–13). GW170817 can be used as a standard siren14–18, combining the distance inferred purely from the gravitational-wave signal with the recession velocity arising from the electromagnetic data to determine the Hubble constant. This quantity, representing the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Our measurements do not require any form of cosmic ‘distance ladder’19; the gravitational-wave analysis directly estimates the luminosity distance out to cosmological scales. Here we report H0 = kilometres per second per megaparsec, which is consistent with existing measurements20,21, while being completely independent of them

Localization and Broadband Follow-up of the Gravitational-wave Transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams. </p

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave transient was identified in data recorded by the Advanced LIGO detectors on 2015 September 14. The event candidate, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the gravitational wave data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network Circulars, giving an overview of the participating facilities, the gravitational wave sky localization coverage, the timeline and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the electromagnetic data and results of the electromagnetic follow-up campaign will be disseminated in the papers of the individual teams

The epidemiology of cephalosporin allergy labels in pediatric primary care

Abstract Background: Recent studies have sought to understand the epidemiology and impact of beta-lactam allergy labels on children; however, most of these studies have focused on penicillin allergy labels. Fewer studies assess cephalosporin antibiotic allergy labels in children. The objective of this study was to determine the prevalence, factors associated with, and impact of cephalosporin allergy labels in children cared for in the primary care setting. Methods: Cephalosporin allergy labels were reviewed among children in a dual center, retrospective, birth cohort who were born between 2010 and 2020 and followed in 90 pediatric primary care practices. Antibiotic prescriptions for acute otitis media were compared in children with and without cephalosporin allergies. Results: 334,465 children comprised the birth cohort and 2,877 (0.9%) were labeled as cephalosporin allergic during the study period at a median age of 1.6 years. Third-generation cephalosporins were the most common class of cephalosporin allergy (83.0%). Cephalosporin allergy labels were more common in children with penicillin allergy labels than those without (5.8% vs. 0.6%). Other factors associated with a cephalosporin allergy label included white race, private insurance, presence of a chronic condition, and increased health care utilization. Children with third-generation cephalosporin allergy labels received more amoxicillin/clavulanate (28.8% vs. 10.2%) and macrolides (10.4% vs. 1.9%) and less amoxicillin (55.8% vs. 70.9%) for treatment of acute otitis media than non-allergic peers p < 0.001. Conclusions: One in 100 children is labeled as cephalosporin allergic, and these children receive different antibiotics for the treatment of acute otitis media compared to non-allergic peers